Monoclonal antibodies (mAbs) have become a mainstay of therapy for many cancers. The key effector mechanisms of mAbs are induction of cell death through complement dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody dependent cell-mediated phagocytosis (ADCMP) and in some cases may include induction of apoptosis. The most commonly used mAbs are of mouse origin that have been chimerized or humanized to carry human constant regions (typically the human IgG1 isotype), a requirement for the recruitment of human effector mechanisms.
However, antibody therapy is not completely effective in some applications due to loss of the target surface antigen. For instance, rituximab and ofatumumab are anti-CD20 mAbs that mediate human immune effector mechanisms including CDC as well as ADCC and ADCMP and are approved for patients with Chronic Lymphocytic Leukemia (CLL), a B cell malignancy. Upon infusion of either of these antibodies, complement protein is deposited on the cell surface of CLL cells and a subset of the cells is killed; however, other CLL cells escape, having lost CD20 expression due to a process called trogocytosis by which antibody-CD20 complexes are pulled off the CLL cell surface by immune cells that bind the Fe-portion of the mAb. The process of trogocytosis leading to antigen loss is not limited to anti-CD20 antibodies or lymphoma but appears to be a common event in mAb therapy.
Accordingly, there is a need for new antibody therapies that can overcome problems associated with loss of the targeted antigen.